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Alzheimer's Disease Reviews: 2006
Zilkova, M., P. Koson, et al. (2006). "The hunt for dying neurons: insight into the neuronal loss in Alzheimer's disease." Bratisl Lek Listy 107(9-10): 366-73.
Neuronal loss is one of the major pathological hallmarks of neurodegenerative disorders including Alzheimer's disease (AD). Using rigorous quantitative methods, the distinct pattern of neuronal loss in pathological conditions such as neurodegeneration and in normal aging was clearly shown. Furthermore, the decrease of total neuronal numbers correlated in a considerable extent with the presence of neurofibrillary degeneration in the same brain regions. However, it appears that neurofibrillary tangles are not the only cause of reduction of neuronal populations, but also alternative triggers could induce neuronal death in this disease. Various inducers, most probably, activate different cell death pathways. Recently, apoptosis has been implicated as a possible mechanism for neuronal death. There is essentially no evidence of apoptosis in AD that would meet all criteria of its classical definition. Therefore it was suggested, that other modes of cell death could contribute to neuronal loss in AD and related disorders (Tab. 2, Ref. 70).
Zilka, N., M. Ferencik, et al. (2006). "Neuroinflammation in Alzheimer's disease: protector or promoter?" Bratisl Lek Listy 107(9-10): 374-83.
Alzheimer's disease (AD) is an irreversible, progressive and degenerative disorder that destroys the higher structures of the brain. Prominent neuropathologic features of AD are senile plaques, neurofibrillary tangles, synaptic and neuronal loss. There is mounting evidence that chronic inflammatory processes play a fundamental role in the progression of neuropathological changes of AD. It has been shown, that there is a reciprocal relationship between the local inflammation and senile plaques (SPs) and neurofibrillary tangles (NFTs). The major players involved in the inflammatory process in AD are thought to be the microglia and the astrocytes. The process of the activation of glia is characteristized by upregulation or newly expression of a variety of molecules involved in inflammatory response including cytokines, various components of the complement cascade, acute phase reactants, proteases and protease inhibitors, and neurotoxic products. The importance of inflammation in the pathogenesis of AD was indirectly confirmed by epidemiological investigations that revealed a decreased incidence of AD in subjects using anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs). However clinical trials designed to inhibit inflammation have failed in the treatment of AD patients suggesting that anti-inflammatory agents have more protective than therapeutic effect. Despite the ongoing research the extent to which neuroinflammation contributes to disease pathogenesis is still not fully understood. Moreover it is also not clear whether the inflammation in AD brains represent a protective reaction to neurodegeneration or it is rather a destructive process that contributes to further loss of brain function. (Ref. 117).
Ziani-Cherif, C., B. Mostefa-Kara, et al. (2006). "Gamma-secretase as a pharmacological target in Alzheimer disease research: when, why and how?" Curr Pharm Des 12(33): 4313-35.
Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (Abeta peptides) in the form of senile plaques as well as neurofibrillary tangles (NFTs) in the brain. In the amyloidogenic pathway, the amyloid-beta precursor protein (APP) is cleaved by beta-secretase first, followed by gamma-secretase cleavage producing therefore Abeta. This review summarizes the recent findings in the AD field and focuses on the different gamma-secretase inhibitors that have been developed as a therapeutic approach toward AD.
Zhu, X., G. Perry, et al. (2006). "Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease." J Alzheimers Dis 9(2): 147-53.
A number of mitochondrial and metabolic abnormalities were identified in the hippocampal neurons of Alzheimer disease compared to age-matched controls. Hippocampal neurons are the most vulnerable to disease-associated pathology (i.e., cell death and proteinaceous lesions) and contain numerous markers of oxidative stress. Interestingly we found that the levels of mitochondrial DNA and cytochrome oxidase-1 in these neurons are markedly increased compared with those of age-matched control brains, even though the number of mitochondria per neuron is decreased. We hypothesize that the increased levels of mitochondrial DNA and cytochrome oxidase-1 may reflect an attempt by oxidatively-challenged neurons to replicate mitochondria, albeit unsuccessfully, as a response to the energetic/oxidative stress. Indeed, in this context, numerous signs of mitosis are observed in pyramidal neurons. Mitotic signals that promote cell cycle re-entry might be expected to also signal the synthesis of new mitochondria. Alternatively, these abnormalities may indicate altered turnover of mitochondrial components as a result of reduced degradation of mitochondrial byproducts or altered mitochondrial transport that redistributes mitochondrial DNA and cytochrome oxidase-1 to the cell body.
Zhu, X., A. K. Raina, et al. (2006). "Apoptosis in Alzheimer disease: a mathematical improbability." Curr Alzheimer Res 3(4): 393-6.
Neuronal cell dysfunction and death are cardinal features of Alzheimer disease and a great deal of effort is being expended not only to understand factors involved in the cause and progression of disease (i.e., disease initiators and propagators) but, ultimately, the precise mechanism by which neurons die (for want of a better word, the terminators). Understanding each and every component of the complex pathway that ultimately leads to disease (a clinical phenotype) is clearly of paramount importance for the development of effective therapeutic strategies. Of particular intrigue for many scientists, perhaps the more macabre among us, has been to decipher the final event - namely cell death. Broadly speaking, cell death falls into two categories, apoptotic and necrotic. The former, apoptosis, by definition, is a controlled event; thereby offering the potential for intervention, whereas necrosis is a more stochastic process. Since many of the propagators and exacerbators involved in Alzheimer disease are pro-apoptotic, it is not surprising that certain aspects of apoptosis are evident. However, it would be a mistake to call this apoptosis. In fact, as reviewed herein, the chronic course of disease together with the necessarily slow rate of neuronal death makes apoptotic cell death in Alzheimer disease a mathematical improbability. The numbers simply do not add up.
Zhang, H. Y. (2006). "Same causes, same cures." Biochem Biophys Res Commun 351(3): 578-81.
Thanks to the continuing bio-medicinal efforts, similar causes underlying the pathogenesis of Alzheimer's disease (AD) and prion diseases (PDs) have been revealed, which include oxidative stress, excessive transition metal ions, and misfolded/aggregated proteins. Therefore, the therapeutic strategy for one disease may be effective for the other. More interestingly, accumulating evidence indicates that not just the strategies but also the prescriptions may be shared by AD and PD treatments. In this review, we first summarize the known dual fighters against AD and PDs (which include antioxidants, metal chelators, and protein aggregation inhibitors), and then indicate that some super-dual-fighters may hit multiple targets implicated in AD and PDs, whose structural features highlight the importance of aromatic moiety and phenolic groups. These findings not only provide important clues to accelerating the screening of anti-AD and anti-PDs drugs but also help to understand the etiology of AD and PDs.
Zablocka, A. (2006). "[Alzheimer's disease as neurodegenerative disorder]." Postepy Hig Med Dosw (Online) 60: 209-16.
Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder. AD patients are affected by cognitive and memory deterioration. Cerebral degeneration, with selective neuronal death induced by extracellular amyloid deposits in the form of senile plaques and intracellular neurofibrillary tangles composed of helical paired tau protein, is the best-studied pathological event related to AD. Presenilins and apolipoprotein E are other neurotoxic agents involved in the pathogenesis of AD. A large body evidence has shown that permanent activation of glial cells in the brains of AD patients promotes the production of excessive quantities of free radicals, nitric oxide, and cytokines which could be detrimental to neuronal cells. Damage to the blood-brain barrier by inflammatory processes result in the influx of peripheral immune system cells and local immune reactions. Inhibition of ROS and NO overproduction as well as endogenic regulation of cytokine induction could be of therapeutic importance and delay neurodegeneration in AD.
Yu, F., A. M. Kolanowski, et al. (2006). "Improving cognition and function through exercise intervention in Alzheimer's disease." J Nurs Scholarsh 38(4): 358-65.
PURPOSE: To analyze the effects of cognition on function and to explore the potential of aerobic exercise for promoting cognitive and functional capacities. DESIGN: Integrative review of literature. METHODS: Studies were selected based on an extensive search of electronic databases and manual cross-referencing for 1980 to 2006, using the combination of key words: Alzheimer's disease (AD), dementia, or cognitive impairment with function or activities of daily living. FINDINGS: Three broad themes were identified from the literature analysis. First, global cognition has mainly been used to examine the effect of cognition on function, indicating an assumption that functional decline progresses in a hierarchical manner in AD. Second, specific cognitive domains affect functional decline in different ways. Executive functioning might have more effect on function than does memory. Third, aerobic exercise might promote cognitive and functional capacities in people with AD by modifying neuropathological changes in the brain. CONCLUSIONS: Specific cognitive domains such as executive functioning are important for understanding function in people with AD and are potentially modifiable by aerobic exercise.
Youdim, M. B. (2006). "The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30." Curr Alzheimer Res 3(5): 541-50.
The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin.
Youdim, M. B., T. Amit, et al. (2006). "Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil." Neurotox Res 10(3-4): 181-92.
The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of several multifunction drugs. These include ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], which combines the pharmacophore-neuroprotective effects of rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine or iron chelating moiety such as M30. In the case of M30 the pharmacophore of brain permeable iron chelator VK-28 plus the MAO inhibitor-neuroprotective propargylamine moiety of rasagiline are combined in a single molecule as a potential treatment for Alzheimer's disease, Lewy body disease, and Parkinson's disease with dementia. Here, we discuss the activities of ladostigil in terms of its cholinesterase cognitive enhancing potential, antiParkinson, antidepressant, neuroprotection and APP (amyloid precursor protein) processing potential. One major attribute of ladostigil is its neuroprotective activity in neuronal cell cultures and in vivo. Employing an apoptotic model of neuroblastoma SK-N-SH cells, the molecular mechanism of its neuroprotective activity has been determined. The current studies show that ladostigil significantly decreased apoptosis via inhibition of the cleavage and prevention of caspase-3 activation through a mechanism related to regulation of the Bcl-2 family proteins, resulting in reduced levels of Bad and Bax and induced levels of Bcl-2. In addition, ladostigil elevated the levels of pPKC(pan). We have also followed the regulation of APP processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP, as well as stimulated the release of the non-amyloidogenic soluble APP (sAPPalpha) into the conditioned medium via a established protein kinsae C-MAPkinase dependent pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor lacking MAO inhibitory activity, exerted similar neuroprotective properties and APP processing, suggesting that the mode of action is independent of MAO inhibition. These effects were shown to reside in the propargylamine moiety. These findings indicate that the dual actions of the anti-apoptotic-neuroprotective activity and the ability to modulate APP processing, could make ladostigil a potentially valuable drug for the treatment of Alzheimer's disease.
Yoshimura, T., N. Arimura, et al. (2006). "Molecular mechanisms of axon specification and neuronal disorders." Ann N Y Acad Sci 1086: 116-25.
A cardinal feature of neurons is the morphological polarity of neurons with serious functional implications. Typically, a neuron has a single axon and several dendrites. Neuronal polarity is essential for the unidirectional signal flow from somata or dendrites to axons in neurons. The initial event in establishing a polarized neuron is the specification of a single axon. Although researchers are accumulating a catalog of structural, molecular, and functional differences between axons and dendrites, we are only now beginning to understand the molecular mechanisms involved in the establishment of neuronal polarity. We have described recent advances in the understanding of cellular events in the early development of an axon and dendrites. Several groups, including ours, reported that the phosphatidylinositol 3-kinase (PI3-kinase)/Akt (also called protein kinase B)/glycogen synthase kinase-3beta (GSK-3beta)/collapsin response mediator protein-2 (CRMP-2) pathway is important for axon specification and elongation. Recent studies have revealed the roles that Rho family small GTPases, the Par complex, and cytoskeleton-related proteins play in the initial events of neuronal polarization downstream of PI3-kinase. We discuss the roles of polarity-regulating molecules and the potential mechanisms underlying the specification of an axon and dendrites. Polarity-regulating molecules participate in various neuronal disorders. In this review, the signal transduction of GSK-3beta and CRMP-2 is introduced as a new target for the treatment of Alzheimer's disease (AD) and nerve injury. These findings may help clarify causes of and treatments aimed at reversing AD and nerve injury.
Yokel, R. A. (2006). "Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration." J Alzheimers Dis 10(2-3): 223-53.
The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
Yan, S. D., W. C. Xiong, et al. (2006). "Mitochondrial amyloid-beta peptide: pathogenesis or late-phase development?" J Alzheimers Dis 9(2): 127-37.
Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-beta peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology.
Yamauchi, T. (2006). "[Molecular mechanism of the regulation of neuronal function based on Ca2+/calmodulin-dependent protein kinase II]." Seikagaku 78(9): 840-52.
Wyss-Coray, T. (2006). "Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's." Curr Alzheimer Res 3(3): 191-5.
Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by the loss of large numbers of forebrain neurons. There are currently no effective AD treatments available and the cause of the disease is unknown in the majority of cases. Because normal neuronal maintenance and survival depends on stimulation of key signaling pathways by a number of neurotrophic factors it has been postulated that reduced signaling by or expression of these factors may promote neurodegeneration. Growing evidence suggests that the transforming growth factor-beta (TGF-beta) signaling pathway may be one such neurotrophic pathway that meets important protective and survival roles in neurons. Here I explore this evidence and discuss the pathway as a potential target for the treatment of neurodegeneration and AD.
Wyss-Coray, T. (2006). "Inflammation in Alzheimer disease: driving force, bystander or beneficial response?" Nat Med 12(9): 1005-15.
Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.
Wu, J. C., Z. Q. Liang, et al. (2006). "Quality control system of the endoplasmic reticulum and related diseases." Acta Biochim Biophys Sin (Shanghai) 38(4): 219-26.
The quality control (QC) system of the endoplasmic reticulum (ER) is an important monitoring mechanism in the protein maturation process, which ensures export of properly folded proteins from the ER. Incorrectly or incompletely folded proteins are retained in the ER for refolding or degradation by the ER-residing proteasome. The calnexin/calreticulin cycle and ER-associated degradation are the key elements in QC. These two mechanisms work together to allow incorrectly folded proteins have additional opportunities to achieve their native conformations. The QC dysfunction is involved in many diseases caused by mutant proteins, many of which are causes of neurodegenerative disorders. A better understanding of molecular regulation in the QC system will uncover the molecular pathogenic mechanisms of many diseases caused by protein misfolding and help discover novel strategies for preventing or treating these diseases.
Wu, W. and S. A. Small (2006). "Imaging the earliest stages of Alzheimer's disease." Curr Alzheimer Res 3(5): 529-39.
Historical progress in medicine can be charted along the lines of technical innovations that have visualized the invisible. One hundred years ago, Alois Alzheimer exploited newly developed histological stains to visualize his eponymonous disease in dead tissue under the microscope. Now, as we are entering the second century of Alzheimer's disease research, technical innovation has endowed us with a range of in vivo imaging techniques that promise to visualize Alzheimer' disease in living people. The earliest stage of Alzheimer's disease is characterized by cell-sickness, not cell-death, and can occur before the deposition of amyloid plaques or neurofibrillary tangles. In principle, 'functional' imaging techniques might be able to detect this early stage of the disease, a stage that was invisible to Alzheimer himself. Here, we will first define the neurobiological meaning of 'function' and then review the different approaches that measure brain dysfunction in Alzheimer' disease.
Wright, T. M. (2006). "Tramiprosate." Drugs Today (Barc) 42(5): 291-8.
Current treatment options for patients with Alzheimer's disease are limited to providing symptomatic relief, with no effects on the underlying pathophysiology. However, a greater understanding of the importance of beta-amyloid peptides (Abeta) in the pathogenesis of this disease has led to the investigation of a number of potential antiamyloid therapies, of which tramiprosate (Neurochem Inc.) is in the most advanced stage of development. Tramiprosate is a glycosaminoglycan (GAG) mimetic designed to interfere with the actions of Abeta early in the cascade of amyloidogenic events. Preclinical data have shown that tramiprosate reduces brain and plasma levels of Abeta, prevents fibril formation and exerts cytoprotective effects in the brain. The pharmacological effects have also been demonstrated in clinical trials of patients with mild to moderate Alzheimer's disease. Promising findings for the efficacy of tramiprosate, indicated by improvement or stabilization of cognitive function, have been shown in phase II clinical trials and open-label extensions of these studies. Furthermore, tramiprosate appears to be well tolerated with no reports of safety concerns. This article reviews the unique mode of action of tramiprosate and summarizes the available clinical information on the effects of tramiprosate in patients with Alzheimer's disease.
Wong, L. F., L. Goodhead, et al. (2006). "Lentivirus-mediated gene transfer to the central nervous system: therapeutic and research applications." Hum Gene Ther 17(1): 1-9.
The management of disorders of the nervous system remains a medical challenge. The key goals are to understand disease mechanisms, to validate therapeutic targets, and to develop new therapeutic strategies. Viral vector-mediated gene transfer can meet these goals and vectors based on lentiviruses have particularly useful features. Lentiviral vectors can deliver 8 kb of sequence, they mediate gene transfer into any neuronal cell type, expression and therapy are sustained, and normal cellular functions in vitro and in vivo are not compromised. After delivery into the nervous system they induce no significant immune responses, there are no unwanted side effects of the vectors per se to date, and manufacturing and safety testing for clinical applications are well advanced. There are now numerous examples of effective long-term treatment of animal models of neurological disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, motor neuron diseases, lysosomal storage diseases, and spinal injury, using a range of therapeutic genes expressed in lentiviral vectors. Significant issues remain in some areas of neural gene therapy including defining the optimum therapeutic gene(s), increasing the specificity of delivery, regulating expression of potentially toxic genes, and designing clinically relevant strategies. We discuss the applications of lentiviral vectors in therapy and research and highlight the essential features that will ensure their translation to the clinic in the near future.
Wolozin, B., J. Manger, et al. (2006). "Re-assessing the relationship between cholesterol, statins and Alzheimer's disease." Acta Neurol Scand Suppl 185: 63-70.
This communication integrates the purported role of cholesterol and statins in Alzheimer's disease (AD) with recent data. Meta-analysis of association studies relevant to AD indicates that apolipoprotein (apo)E4 is the only cholesterol-related polymorphism that shows clear association with AD. This suggests that the effect of apoE4 on the pathophysiology of AD occurs via a mechanism that is not directly related to cholesterol, such as fibrillization of Abeta. Despite the lack of genetic association, cholesterol and statins clearly modulate amyloid precursor protein (APP) processing in cell culture and animal models. Statins appear to act by a pleiotropic mechanism, involving both cholesterol (via lipid rafts) and isoprenylation. The pleiotropic mechanism of statin action clarifies conflicting data from clinical studies, where statins exert an action on Abeta and AD that might be dose dependent because of actions on both cholesterol and isoprenylation. Reduced isoprenylation can also inhibit inflammation. Our own studies of brains from Alzheimer subjects +/- statins indicate that statins inhibit inflammation in humans but might not reduce cerebral Abeta load. These results suggest that the primary action of statins in humans with AD might be to reduce inflammation rather than decrease Abeta load.
Wolozin, B. and M. M. Bednar (2006). "Interventions for heart disease and their effects on Alzheimer's disease." Neurol Res 28(6): 630-6.
OBJECTIVES: To review the contributions of cardiovascular disease to Alzheimer's disease and vascular dementia. METHODS: Review of the literature. RESULTS: Alzheimer's disease and vascular dementia both share significant risk attributable to cardiovascular risk factors. Hypertension and hypercholesterolemia at midlife are significant risk factors for both subsequent dementia. Diabetes and obesity are also risk factors for dementia. Stressful medical procedures, such as coronary artery bypass and graft operations also appear to contribute to the risk of Alzheimer's disease. Apolipoprotein E is the major risk factor for Alzheimer's disease. Apolipoprotein E does not appear to contribute to Alzheimer's disease by increasing serum cholesterol, but it might contribute to the disease through a mechanism involving both Abeta and an increase in neuronal vulnerability to stress. DISCUSSION: The strong association of cardiovascular risk factors with Alzheimer's disease and vascular dementia suggest that these diseases share some biologic pathways in common. The contribution of cardiovascular disease to Alzheimer's disease and vascular dementia suggest that cardiovascular therapies might prove useful in treating or preventing dementia. Antihypertensive medications appear to be beneficial in preventing vascular dementia. Statins might be beneficial in preventing the progression of dementia in subjects with Alzheimer's disease.
Wojtal, K., M. K. Trojnar, et al. (2006). "Endogenous neuroprotective factors: neurosteroids." Pharmacol Rep 58(3): 335-40.
Neurosteroids are a group of steroid hormones synthesized by the brain in the presence of steroidogenic enzymes. Specific neurosteroids modulate function of several receptors, and also regulate growth of neurons, myelinization and synaptogenesis in the central nervous system. Some neurosteroids have been shown to display neuroprotective properties, which may have important implications for their potential use in the treatment of various neuropathologies such as: age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann-Pick type C disease (NP-C). This paper focuses on neuroprotection afforded by neurosteroids.
Wirth, T. and S. Yla-Herttuala (2006). "Gene technology based therapies in the brain." Adv Tech Stand Neurosurg 31: 3-32.
Gene therapy potentially represents one of the most important developments in modern medicine. Gene therapy, especially of cancer, has created exciting and elusive areas of therapeutic research in the past decade. In fact, the first gene therapy performed in a human was not against cancer but was performed to a 14 year old child suffering from adenosine deaminase (ADA) deficiency. In addition to cancer gene therapy there are many other diseases and disorders where gene therapy holds exciting and promising opportunities. These include amongst others gene therapy within the central nervous system and the cardiovascular system. Improvements of the efficiency and safety of gene therapy is the major goal of gene therapy development. After the death of Jesse Gelsinger, the first patient in whom death could be directly linked to the viral vector used for the treatment, ethical doubts were raised about the feasibility of gene therapy in humans. Therefore, the ability to direct gene transfer vectors to specific target cells is also a crucial task to be solved and will be important not only to achieve a therapeutic effect but also to limit potential adverse effects.
Williams, B. J., M. Eriksdotter-Jonhagen, et al. (2006). "Nerve growth factor in treatment and pathogenesis of Alzheimer's disease." Prog Neurobiol 80(3): 114-28.
The etiology of Alzheimer's disease (AD) is still unknown. In addition, this terrible neurodegenerative disease will increase exponentially over the next two decades due to longer lifespan and an aging "baby-boomer" generation. All treatments currently approved for AD have moderate efficacy in slowing the rate of cognitive decline in patients, and no efficacy in halting progression of the disease. Hence, there is an urgent need for new drug targets and delivery methods to slow or reverse the progression of AD. One molecule that has received much attention in its potential therapeutic role in AD is nerve growth factor (NGF). This review will demonstrate data from humans and animals which promote NGF as a potential therapeutic target by (1) outlining the hypothesis behind using NGF for the treatment of AD, (2) reviewing both the normal and AD altered signaling pathways and effects of NGF in the central nervous system (CNS), and (3) examining the results of NGF treatment obtained from animal models of AD and AD patients.
Whitfield, J. F. (2006). "Can statins put the brakes on Alzheimer's disease?" Expert Opin Investig Drugs 15(12): 1479-85.
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which initiates the syntheses of cholesterol and isoprenoid lipids that are needed to provide amyloid peptides for the amyloid cascade. This cascade is believed to induce sporadic or late-onset Alzheimer's disease, which accounts for 90 - 95% of Alzheimer's disease sufferers. Cholesterol is also the prime driver of cerebrovascular disease that (along with amyloid peptides) increasingly appears to be linked to the cognitive deterioration of Alzheimer's disease. Cholesterol is needed to make the lipid rafts that are the platforms for isoprenoid-dependent assembly and activation of raftophilic beta- and gamma-secretases that work in tandem to excise dangerous 40 and 42 amino acid amyloid-beta (Abeta) fragments from amyloid precursor protein, the transmembrane amyloid precursor glycoprotein. When they are excessively produced and can no longer be effectively destroyed or otherwise cleared from the hypoperfused ageing brain, the Abeta42 fragments released from the active synaptic terminals of normally busy neurons (and from stressed neurons unsuccessfully trying to proliferate and producing disruptive tangles of hyperphosphorylated tau-proteins) aggregate into neuritic plaques, which activate glial cells. The pro-inflammatory cytokines and growth factors from the glial cells further damage and kill neurons. As statins strike at several parts of the Alzheimer's disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer's disease development) should slow or even prevent the progression of Alzheimer's disease. Indeed, there is some evidence of a significantly reduced incidence of Alzheimer's disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects. To be certain of this, there must be more multi-year trials to specifically assess the effects of statins on sporadic Alzheimer's disease.
Whitehouse, P. J. (2006). "The end of AD. Part 3." Alzheimer Dis Assoc Disord 20(4): 195-8.
White, A. R., K. J. Barnham, et al. (2006). "Metal homeostasis in Alzheimer's disease." Expert Rev Neurother 6(5): 711-22.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal dysfunction and the formation of amyloid plaques in the brain. Although the pathological processes resulting in the onset and progression of AD are not well understood, there is a growing body of evidence to support a central role for biometals in many critical aspects of the illness. Recent reports have described the exciting development of potential therapeutic agents based on the modulation of metal bioavailability. The metal ligand, clioquinol has demonstrated promising results in animal models and small clinical trials and a new generation of metal ligand-based therapeutics are currently under development. However, further research is necessary to fully understand the complex and interdependent pathways of biometal homeostasis and amyloid metabolism in AD. This information will be vital for the development of safe and effective metal-based pharmaceuticals for the treatment of AD and, potentially, other neurodegenerative disorders.
White, L. and L. Launer (2006). "Relevance of cardiovascular risk factors and ischemic cerebrovascular disease to the pathogenesis of Alzheimer disease: a review of accrued findings from the Honolulu-Asia Aging Study." Alzheimer Dis Assoc Disord 20(3 Suppl 2): S79-83.
Werheid, K. and A. I. Thone-Otto (2006). "[Cognitive training in Alzheimer's dementia]." Nervenarzt 77(5): 549-57.
Memory rehabilitation in dementia patients is gaining importance. Among the increasing number of people affected by Alzheimer's dementia (AD), the number detected in early stages of the disease is growing disproportionately quickly. The reasons are obvious: improved clinical assessment in the initial disease stage, increased sensitization of the elderly towards cognitive deficits, and the prescription of drugs retarding cognitive decline. Given the limited success of early training programs in the 1980s, skepticism towards cognitive training in dementia is still common among clinicians. However, recent international studies in the field give reason for cautious optimism. Memory therapy in the early-to-moderate stages of AD can be successful, if it is tailored to patients' individual daily problems and based on their residual cognitive capacities. The present paper gives an overview of recent findings in clinical and cognitive neuroscience which have led to a conceptual change in the memory rehabilitation of patients with dementia. Based on a review of general principles and rehabilitation techniques proven successful in recent research, recommendations are formulated for future studies evaluating cognitive therapy in dementia.
Wenk, G. L. (2006). "Neuropathologic changes in Alzheimer's disease: potential targets for treatment." J Clin Psychiatry 67 Suppl 3: 3-7; quiz 23.
The cognitive symptoms of Alzheimer's disease (AD) are believed to be caused not only by the loss of neurons in the cholinergic and glutamatergic neural systems but also by the irregular functioning of surviving neurons in these 2 systems. Aberrant cholinergic functioning in AD has been linked to deficits in the neurotransmitter acetylcholine, while AD-related abnormalities in glutamatergic signaling have been attributed to excitotoxicity caused by the persistent, low-level stimulation of glutamatergic neurons via the chronic influx of Ca(2+) ions through the N-methyl-D-aspartate (NMDA) receptor calcium channel. Glutamatergic abnormalities in AD can be corrected to some extent by the NMDA receptor antagonist memantine, an agent whose therapeutic efficacy is believed to be related to its low to moderate level of affinity for the NMDA receptor calcium channel, a characteristic that allows memantine to prevent excessive glutamatergic stimulation while still permitting normal glutamate-mediated neurotransmission to take place. Although the mechanism underlying the chronic stimulation of glutamatergic neurons in AD has yet to be elucidated, one hypothesis is that the characteristic neuropathologic features of AD -- beta-amyloid deposits and neurofibrillary tangles -- induce brain inflammation, which in turn impairs glutamatergic receptor function in such a way that the ability of these receptors to prevent the influx of Ca(2+) in the absence of an appropriate presynaptic signal is compromised. If this hypothesis is correct, and if it is correct that beta-amyloid deposits and neurofibrillary tangles arise long before the symptomatic onset of AD, then memantine, with its ability to alleviate glutamatergic receptor overstimulation, would be expected to provide therapeutic benefits beginning from the earliest stages of the disease.
Wenk, G. L., C. G. Parsons, et al. (2006). "Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine." Behav Pharmacol 17(5-6): 411-24.
Glutamatergic neurotransmission is critical to normal learning and memory and when the activity of glutamate neurons becomes excessive, or the normal function of its primary receptors becomes dysfunctional, this may lead to pathological changes associated with age-related neurodegenerative diseases. Anomalous glutamatergic activity associated with Alzheimer's disease may be due to a postsynaptic receptor and downstream defects that produce inappropriately timed or sustained glutamate activation of N-methyl-D-aspartate receptors, leading to neuronal injury and death and cognitive deficits associated with dementia. The mechanisms leading to the condition of chronically depolarized membranes on vulnerable neurons in the Alzheimer's disease brain are likely due to a complex interaction between oxidative stress, mitochondrial failure, chronic brain inflammation and the presence of amyloid-beta and hyperphosphorylated-tau; each of these factors are highly interrelated with each other and are discussed with an emphasis upon potential therapeutic mechanisms underlying the neuroprotective actions of memantine.
Weisman, D., E. Hakimian, et al. (2006). "Interleukins, inflammation, and mechanisms of Alzheimer's disease." Vitam Horm 74: 505-30.
Alzheimer's disease (AD) is the most common progressive neurodegenerative form of dementia in the elderly and is characterized neuropathologically by neurofibrillary tangles (NFT), amyloid neuritic plaques (NP), and prominent synaptic and eventually neuronal loss. Although the molecular basis of AD is not clearly understood, a neuroinflammatory process, triggered by Abeta42, plays a central role in the neurodegenerative process. This inflammatory process is driven by activated microglia, astrocytes and the induction of proinflammatory molecules and related signaling pathways, leading to both synaptic and neuronal damage as well as further inflammatory cell activation. Epidemiologic data as well as clinical trial evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may decrease the incidence of AD, further supporting a role for inflammation in AD pathogenesis. Although the precise molecular and cellular relationship between AD and inflammation remains unclear, interleukins and cytokines might induce activation of signaling pathways leading to futher inflammation and neuronal injury. This chapter will discuss the association between interleukins and neurodegeneration in AD and highlight the significance of genetic and clinical aspects of interleukins in disease expression and progression. As part of an emerging inflammatory signaling network underlying AD pathogenesis, beta-amyloid (Abeta) stimulates the glial and microglial production of interleukins and other cytokines, leading to an ongoing inflammatory cascade and contributing to synaptic dysfunction and loss, and later, neuronal death. Inflammatory pathways involving interleukin and cytokine signaling might suggest potential targets for intervention and influence the development of novel therapies to circumvent synaptic and neuronal dysfunction ultimately leading to AD neurodegeneration.
Weiner, H. L. and D. Frenkel (2006). "Immunology and immunotherapy of Alzheimer's disease." Nat Rev Immunol 6(5): 404-16.
Although Alzheimer's disease is considered to be a degenerative brain disease, it is clear that the immune system has an important role in the disease process. As discussed in this Review, immune-based therapies that are designed to remove amyloid-beta peptide from the brain have produced positive results in animal models of the disease and are being tested in humans with Alzheimer's disease. Although immunotherapy holds great promise for the treatment of Alzheimer's disease, clinical trials of active amyloid-beta vaccination of patients with Alzheimer's disease were discontinued after some patients developed meningoencephalitis. New immunotherapies using humoral and cell-based approaches are currently being investigated for the treatment and prevention of Alzheimer's disease.
Webber, K. M., G. Casadesus, et al. (2006). "The cell cycle and hormonal fluxes in Alzheimer disease: a novel therapeutic target." Curr Pharm Des 12(6): 691-7.
Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.
Watson, G. S. and S. Craft (2006). "Insulin resistance, inflammation, and cognition in Alzheimer's Disease: lessons for multiple sclerosis." J Neurol Sci 245(1-2): 21-33.
Insulin resistance (reduced ability of insulin to stimulate glucose utilization) is common in North American and Europe, where as many as one third of all older adults suffer from prodromal or clinical type 2 diabetes mellitus. It has long been known that insulin-resistant conditions adversely affect general health status. A growing body of findings suggests that insulin contributes to normal brain functioning and that peripheral insulin abnormalities increase the risk for memory loss and neurodegenerative disorders such as Alzheimer's disease. Potential mechanisms for these effects include insulin's role in cerebral glucose metabolism, peptide regulation, modulation of neurotransmitter levels, and modulation of many aspects of the inflammatory network. An intriguing question is whether insulin abnormalities also influence the pathophysiology of multiple sclerosis (MS), an autoimmune disorder characterized by elevated inflammatory biomarkers, central nervous system white matter lesions, axonal degeneration, and cognitive impairment. MS increases the risk for type 1 diabetes mellitus. Furthermore, the lack of association between MS and type 2 diabetes may suggest that insulin resistance affects patients with MS and the general population at the same alarming rate. Therefore, insulin resistance may exacerbate phenomena that are common to MS and insulin-resistant conditions, such as cognitive impairments and elevated inflammatory responses. Interestingly, the thiazolidinediones, which are used to treat patients with type 2 diabetes, have been proposed as potential therapeutic agents for both Alzheimer's disease and MS. The agents improve insulin sensitivity, reduce hyperinsulinemia, and exert anti-inflammatory actions. Ongoing studies will determine whether thiazolidinediones improve cognitive functioning for patients with type 2 diabetes or Alzheimer's disease. Future studies are needed to examine the effects of thiazolidinediones on patients with MS.
Wang, R., H. Yan, et al. (2006). "Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine." Acta Pharmacol Sin 27(1): 1-26.
Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.
Wang, J. Z. and Z. F. Wang (2006). "Role of melatonin in Alzheimer-like neurodegeneration." Acta Pharmacol Sin 27(1): 41-9.
Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.
Wang, Y. J., H. D. Zhou, et al. (2006). "Clearance of amyloid-beta in Alzheimer's disease: progress, problems and perspectives." Drug Discov Today 11(19-20): 931-8.
Alzheimer's disease (AD) is the most common form of senile dementia and the fourth highest cause of disability and death in the elderly. Amyloid-beta (Abeta) has been widely implicated in the etiology of AD. Several mechanisms have been proposed for Abeta clearance, including receptor-mediated Abeta transport across the blood-brain barrier and enzyme-mediated Abeta degradation. Moreover, pre-existing immune responses to Abeta might also be involved in Abeta clearance. In AD, such mechanisms appear to have become impaired. Recently, therapeutic approaches for Abeta clearance, targeting immunotherapy and molecules binding Abeta, have been developed. In this review, we discuss recent progress and problems with respect to Abeta clearance mechanisms and propose strategies for the development of therapeutics targeting Abeta clearance.
Walton, K. M., J. E. Chin, et al. (2006). "Galanin function in the central nervous system." Curr Opin Drug Discov Devel 9(5): 560-70.
The peptide galanin is primarily expressed in the central nervous system (CNS) and it is active in a range of models of behavior. The identification of three galanin receptors, whose distribution of expression is distinct but overlapping, is evidence of the complexity of galanin's regulation of neuronal function. The majority of studies examining galanin have used broad methods to identify its function, employing nonselective peptide agonists and antagonists, or transgenic animal models. While these studies were informative, they provided limited insight to the specific receptors mediating the effects of galanin. The recent identification of potent, brain-permeable and selective galanin antagonists suggests it will be possible to gain greater insight into the function of each galanin receptor and their potential as therapeutic targets. This article reviews the roles identified for galanin in the CNS and how ligands of the galanin receptors, both peptidic and small-molecule, have been used to explore the behavioral models that characterize these roles.
Waldron, E., S. Jaeger, et al. (2006). "Functional role of the low-density lipoprotein receptor-related protein in Alzheimer's disease." Neurodegener Dis 3(4-5): 233-8.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by neuronal loss, neurofibrillary tangle formation and the extracellular deposition of amyloid-beta (Abeta) plaques. The amyloid precursor protein (APP) and the enzymes responsible for Abeta generation seem to be the base elements triggering the destructive processes. Initially, the low-density lipoprotein receptor-related protein (LRP) was genetically linked to AD and later it emerged to impact on many fundamental events related to this disease. LRP is not only involved in Abeta clearance but is also the major receptor of several AD-associated ligands, e.g. apolipoprotein E and alpha2-macroglobulin. APP processing is mediated by LRP on many levels. Enhanced APP internalization through LRP decreases cell surface APP levels and thereby reduces APP shedding. As a consequence of increased APP internalization LRP enhances Abeta secretion. These effects could be attributed to the cytoplasmic tails of LRP and APP. The receptors bind via their NPXY motifs to the two PID domains of FE65 and form a tripartite complex. However, it appears that the second NPVY motif of LRP is the one responsible for the observed influence over APP metabolism. A more in-depth knowledge of the mechanisms regulating APP cleavage may offer additional targets for therapeutic intervention.
von Gunten, A., C. Bouras, et al. (2006). "Neural substrates of cognitive and behavioral deficits in atypical Alzheimer's disease." Brain Res Rev 51(2): 176-211.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline that typically affects first memory and later executive functions, language, and visuospatial skills. This sequence of cognitive deterioration is thought to reflect the progressive invasion of the cerebral cortex by the two major pathological hallmarks of AD, neurofibrillary tangles (NFT) and senile plaques (SP), as well as degree of neuronal and synaptic loss. In atypical AD, prominent and early deficits are found in language, motor abilities, frontal and executive capacities, or visuospatial skills. These atypical clinical features are associated with an unusual pattern of NFT or SP formation that predominantly involves cortical areas usually spared in the course of the degenerative process. In an attempt to classify this highly heterogeneous subgroup, the present article provides an overview of clinicopathological analyses in patients with atypical progression of AD symptomatology with special reference to the relationship between specific cognitive and behavioral deficits and hierarchical patterns of AD lesion distribution within the cerebral cortex. On the basis of these representative examples of a cortical circuit-based approach to explore the mechanisms giving rise to AD neuropsychological expression, we also critically discuss the possibility to develop a matrix linking clinical presentations to degeneration of forward and backward long corticocortical pathways in this disorder.
Vogel, T., A. Benetos, et al. (2006). "[Risk factors for Alzheimer: towards prevention?]." Presse Med 35(9 Pt 2): 1309-16.
Recent longitudinal studies have highlighted associations between Alzheimer's disease (AD) and several factors, especially some cardiovascular risk factors, including hypertension, diabetes, diet, obesity, and elevated levels of homocysteine and lipids in the blood. The strongest associations are with hypertension and diabetes. Moderate alcohol consumption also appears to be associated with a decreased risk of incident AD. Studies of the effect of interventions to control these risk factors on the onset and course of dementia report encouraging results about antihypertensive agents and statins. Benefits from other drug therapies such as nonsteroidal antiinflammatory drugs and antioxidants remain uncertain, and initial hopes for hormonal replacement therapy for postmenopausal women have not been confirmed. Physical, cognitive and leisure activities seem to provide protection against incident AD. Cautious interpretation is necessary in view of the possible biases in these studies (confounding factors as well as survival, regression dilution, and indication biases). These epidemiologic data raise questions about the diagnostic boundaries between AD and vascular dementia. Additional studies are needed to validate these concepts and to confirm the possible benefits of preventive measures.
Visser, P. J. (2006). "Role of cognitive testing in disease modifying AD trials." J Nutr Health Aging 10(2): 131-2; discussion 132-3.
Cognitive impairment is a key feature of Alzheimer's disease (AD). Cognitive performance will therefore be an important outcome measure in disease modifying drug trials. However, cognitive assessment also has several limitations such as a large inter and intra individual variability and floor and ceiling effects. To reduce the effect of these limitations on the accuracy with which drug-related changes can be detected, it is proposed to analyse cognitive change using a slope analysis. In addition, it is suggested to use as the main outcome measure for cognitive impairment a neuropsychological compound score that is based on a z-score transformation of a number of well-validated tests. The selection of these tests would depend on a number of study characteristics such as the inclusion criteria and the length of follow-up.
Vetrivel, K. S. and G. Thinakaran (2006). "Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments." Neurology 66(2 Suppl 1): S69-73.
Trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations in the past two decades, since the identification of Abeta as the principal component of brain senile plaques and the cloning of APP cDNA. Tremendous progress has been made in the recent past toward the characterization of beta- and gamma-secretases. Here, we review the salient features of Alzheimer disease amyloidogenesis, and discuss the current knowledge on APP trafficking and amyloidogenic processing of APP in intracellular membrane compartments and microdomains.
Verhey, F. (2006). "Recommendations concerning neuropsychiatric symptoms assessment." J Nutr Health Aging 10(2): 134-5; discussion 135-6.
In the last decades, there has been an increased awareness of the importance of neuropsychiatric symptoms in dementia, as they are highly frequent, put a large burden on the caregiver, and often may lead to early institutionalization. Whereas dementia is still principally defined as a cognitive disorders, neuropsychiatric symptoms are now regarded as an intrinsic aspect of dementia and neurodegenerative processes. The question to be addressed here is what neuropsychiatric assessments should be used in long term trials adhering a disease modifying approach to Alzheimer's Disease (AD). An ideal marker should be valid, be measured reliably, be highly sensitive to change, have a clear correlation with the progression of disease, and have a clear relationship with the neuropathological substrate. In addition, the marker should address particularly the early stages of AD, preferably the prodromal predementia stages.
Verhey, F. R. (2006). "[Pharmacotherapy for Alzheimer's disease]." Tijdschr Psychiatr 48(1): 17-26.
BACKGROUND: So far no causal therapies are available for the treatment of Alzheimer's disease. However, four drugs, namely donepezil, rivastigmine, galantamine and memantine, have been licensed for treating the symptoms of the disease. AIM: To systematically review the efficacy and side-effects of these drugs. METHOD: With the help of Pubmed, Medline and the Cochrane Library the literature was searched systematically. RESULTS: Cholinesterase-inhibitors and memantine do have a beneficial effect on cognition and daily functioning. The effect, however, is limited and the cholinesterase-inhibitors in particular frequently have side-effects. CONCLUSION: Treatment with the new anti-Alzheimer drugs demands a careful and realistic approach. The drugs should not be prescribed in isolation but the treatment needs to be embedded in the entire set of currently available psychosocial intervention techniques.
Vasilevko, V. and D. H. Cribbs (2006). "Novel approaches for immunotherapeutic intervention in Alzheimer's disease." Neurochem Int 49(2): 113-26.
Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Abeta. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Abeta antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of beta-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of beta-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Abeta antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Abeta and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.
Vardy, E. R., I. Hussain, et al. (2006). "Emerging therapeutics for Alzheimer's disease." Expert Rev Neurother 6(5): 695-704.
Alzheimer's disease (AD) is the most common form of dementia, with prevalence and the accompanying socioeconomic impact set to increase over the coming decades. Currently available medications result, at best, in modest cognitive improvement. With increasing understanding of the underlying pathology, new therapeutic targets are being identified at an ever-increasing rate. The key pathological events in the AD brain are deposition of insoluble amyloid-beta peptide (Abeta), formation of neurofibrillary tangles and neuroinflammation leading, ultimately, to neuronal cell death. Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future.
Vandeweerd, C., G. J. Paveza, et al. (2006). "Abuse and neglect in older adults with Alzheimer's disease." Nurs Clin North Am 41(1): 43-55, v-vi.
Elder mistreatment is a serious issue that effects the lives of thousands of older adults and results in emotional difficulties, such as depression,feelings of inadequacy, self-loathing, and lowered self-esteem. It has been shown to result in family distress, impaired life functioning, and difficulties with cognition and has been linked to health problems,such as immunologic dysfunction, and increased mortality. As the population ages, and with it the numbers of persons afflicted by diseases such as Alzheimer's, understanding and recognizing elder mistreatment becomes an important factor in maintaining quality of life for older adults.
van Leeuwen, F. W., E. M. Hol, et al. (2006). "Frameshift proteins in Alzheimer's disease and in other conformational disorders: time for the ubiquitin-proteasome system." J Alzheimers Dis 9(3 Suppl): 319-25.
Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1, unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UB+1 is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1-being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds - enabling us to identify the targets of the UPS in these conformational diseases - may now pave the way for intervention and treatment of AD.
Van Dam, D. and P. P. De Deyn (2006). "Drug discovery in dementia: the role of rodent models." Nat Rev Drug Discov 5(11): 956-70.
Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease have pointed to novel strategies for drug development. Animal models have contributed considerably to these advances, and will have a key role in the evaluation of therapeutics that could have the potential not just to alleviate the dementia associated with Alzheimer's disease, but to modify the disease process. Here, we summarize and critically evaluate current rodent models of dementia, and discuss their role in drug discovery and development.
Van Broeckhoven, C. and S. Kumar-Singh (2006). "Genetics and pathology of alpha-secretase site AbetaPP mutations in the understanding of Alzheimer's disease." J Alzheimers Dis 9(3 Suppl): 389-98.
Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer's disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AbetaPP that have led to our better understanding of the pathogenesis of AD. Specifically, we will discuss how pathologies linked to the Dutch (E693Q) and Flemish AbetaPP (A692G) mutations have helped in understanding the role of CAA in dementia and in the development of dense-core plaques. In addition, this review will also point directions that warrant additional studies.
Valenza, M. and E. Cattaneo (2006). "Cholesterol dysfunction in neurodegenerative diseases: is Huntington's disease in the list?" Prog Neurobiol 80(4): 165-76.
Brain cholesterol is an essential component of cell membranes, and involved in a number of biological functions such as membrane trafficking, signal transduction, myelin formation and synaptogenesis. Given these widespread activities and the knowledge that all brain cholesterol derives from local synthesis, it is not surprising that dysfunctions in cholesterol synthesis, storage, transport and removal may lead to human brain diseases. Some of these diseases emerge as a consequence of genetic defects in the enzymes involved in cholesterol biosynthesis; in other cases, such as Alzheimer's disease, there is a link between cholesterol metabolism and the formation and deposition of amyloid-beta peptide. Emerging evidence indicates that changes in cholesterol synthesis may also occur in Huntington's disease, an inherited, autosomal dominant neurodegenerative disorder that primarily affects striatal neurons of the brain. We here provide an overview of the involvement of cholesterol in normal brain function and its impact on neurodegenerative diseases. In particular, we consider the available clinical, biological and molecular evidence indicating a potential dysregulation of cholesterol homeostasis in Huntington's disease.
Usui, T. (2006). "Pharmaceutical prospects of phytoestrogens." Endocr J 53(1): 7-20.
Interest in the physiologic and pharmacologic role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the classes of compounds known as the phytoestrogens, which embody several groups of non-steroidal estrogens, including isoflavones and lignans that are widely distributed within nature. The impact of dietary phytoestrogens on normal biologic processes was first recognized in sheep. Observations of sheep grazing on fields rich in clover and cheetahs fed high soy diets in zoos suggested that flavonoids and related phytochemicals can affect mammalian health. Endogenous estrogens have an important role not only in the hypothalamic-pituitary-gonadal axis, but also in various non-gonadal systems, such as cardiovascular systems, bone, and central nervous systems, and lipid metabolism. There have been several clinical studies of hormone replacement therapy (HRT) in post-menopausal women to examine whether HRT has beneficial effects on the cardiovascular system, bone fractures, lipid metabolism, and Alzheimer's disease. In addition, estrogen contributes to the development of some estrogen-dependent cancers, such as breast cancer and prostate cancer and the number of patients with these cancers is increasing in developed countries. Although recent mega-studies showed negative results for classical HRT in the prevention of some of these diseases, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers. This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens.
Urbanc, B., L. Cruz, et al. (2006). "Computer simulations of Alzheimer's amyloid beta-protein folding and assembly." Curr Alzheimer Res 3(5): 493-504.
Pathological folding and aggregation of the amyloid beta-protein (Abeta) are widely perceived as central to understanding Alzheimer's disease (AD) at the molecular level. Experimental approaches to study Abeta self-assembly are limited, because most relevant aggregates are quasi-stable and inhomogeneous. In contrast, simulations can provide significant insights into the problem, including specific sites in the molecule that would be attractive for drug targeting and details of the assembly pathways leading to the production of toxic assemblies. Here we review computer simulation approaches to understanding the structural biology of Abeta. We discuss the ways in which these simulations help guide experimental work, and in turn, how experimental results guide the development of theoretical and simulation approaches that may be of general utility in understanding pathologic protein folding and assembly.
Urakami, K. (2006). "[Alzheimer's disease should be treated as a vascular disease]." Nippon Ronen Igakkai Zasshi 43(4): 453-4.
Uhlhaas, P. J. and W. Singer (2006). "Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology." Neuron 52(1): 155-68.
Following the discovery of context-dependent synchronization of oscillatory neuronal responses in the visual system, novel methods of time series analysis have been developed for the examination of task- and performance-related oscillatory activity and its synchronization. Studies employing these advanced techniques revealed that synchronization of oscillatory responses in the beta- and gamma-band is involved in a variety of cognitive functions, such as perceptual grouping, attention-dependent stimulus selection, routing of signals across distributed cortical networks, sensory-motor integration, working memory, and perceptual awareness. Here, we review evidence that certain brain disorders, such as schizophrenia, epilepsy, autism, Alzheimer's disease, and Parkinson's are associated with abnormal neural synchronization. The data suggest close correlations between abnormalities in neuronal synchronization and cognitive dysfunctions, emphasizing the importance of temporal coordination. Thus, focused search for abnormalities in temporal patterning may be of considerable clinical relevance.
Tyler, C. M. and H. J. Federoff (2006). "CNS gene therapy and a nexus of complexity: systems and biology at a crossroads." Cell Transplant 15(3): 267-73.
Gene therapy is a potentially promising new treatment for neurodegenerative disorders such as Alzheimer's disease (AD), which has been difficult to treat with conventional therapeutics. Viral vector-mediated somatic gene therapy is a rapidly developing methodology for providing never before achieved capability to deliver specific genes to the CNS in a highly localized and controlled manner. With the advent and refinements of this technology one focus is directed to which genes are the most appropriate to select for specific disease indications. Nerve growth factor (NGF), a potent survival factor for critical cell populations that degenerate in AD, has been chosen already for clinical gene therapy trials in human AD patients. Much knowledge about the pathophysiological underpinnings of AD is still lacking to make clear which patients may benefit from a gene therapy approach. Moreover, a detailed understanding of sustained NGF action in the normal and diseased CNS needs to be resolved before conclusions can be drawn regarding the utility of NGF gene therapy. Systematic efforts to acquire this new knowledge should compel clinically and biologically sophisticated efforts to advance gene therapy for neurodegenerative diseases.
Twamley, E. W., S. A. Ropacki, et al. (2006). "Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease." J Int Neuropsychol Soc 12(5): 707-35.
Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular.
Turner, R. S. (2006). "Alzheimer's disease." Semin Neurol 26(5): 499-506.
Alzheimer's disease (AD) is the most commonly diagnosed etiology of dementia and may be caused by the progressive accumulation and deposition of neurotoxic Abeta/amyloid plaques and aggregates in brain with aging-the amyloid hypothesis of AD. However, Abeta/amyloid deposition is likely necessary but not sufficient to cause AD, and other putative downstream pathologies, including the aggregation of phospho-tau in neurofibrillary tangles, synaptic and neuronal loss, and glial and inflammatory responses, are likely equally important to AD pathogenesis. The majority of AD is sporadic (> 95%) but the discovery of rare early onset familial forms of AD has been pivotal to our understanding of its pathogenesis and in developing novel therapeutic strategies. Currently available drugs for patients with AD provide modest, temporary, and palliative benefits, but they consistently demonstrate safety and efficacy on cognitive, functional, behavioral, and global outcome measures. Novel potential disease-modifying therapies now in preclinical research or clinical trials may be more effective in preventing or arresting the progressive dementia of AD and will provide a test of the amyloid hypothesis.
Tousseyn, T., E. Jorissen, et al. (2006). "(Make) stick and cut loose--disintegrin metalloproteases in development and disease." Birth Defects Res C Embryo Today 78(1): 24-46.
"A disintegrin and metalloprotease" (ADAM) proteases form a still growing family of about 40 type 1 transmembrane proteins. They are defined by a common modular ectodomain architecture that combines cell deadhesion/adhesion and fusion motifs (disintegrin and cysteine-rich domains), with a Zn-protease domain capped by a large prodomain. Their ectodomain thus strikingly resembles snake venom disintegrin proteases, which by combined integrin blocking and extracellular proteolysis, can cause extensive tissue damage after snake bites. A surprisingly large proportion (13 ADAMs) is exclusively expressed in the male gonads, and only a minority can be found throughout all tissues. As predicted by their amino acid sequence, a major proportion of this family has not maintained a functional protease domain, most probably rendering them into pure adhesion and/or fusion proteins. For most ADAMs, the respective key function has remained elusive. Despite their overall conserved ectodomain structure, ADAMs appear to be subdivided into those with a predominant role in direct adhesion (e.g., ADAMs 1, 2, and 3) and those mainly acting as proteases (e.g., ADAMs 10 and 17). Only for a few of them are functions of more than one domain documented (e.g., ADAM9 in cell fusion and proteolysis). Several ADAMs exist in both membrane-resident and secreted isoforms; the functional significance of this dichotomy is in most cases still unclear. Knockout phenotypes have been informative only in a few cases (ADAMs 1, 2, 10, 12, 15, 17, and 19) and are mainly related to their protease function. A common denominator of ADAM-mediated proteolysis is the ectodomain shedding of a broad spectrum of substrates, including paracrine growth factors like epidermal growth factor receptor (EGFR) ligands, cell adhesion molecules like CD44 or cadherins, and the initiation of regulated intramembrane proteolysis (RIP), whereby the transmembrane fragment of the respective substrate is further cleaved by an intramembrane cleaving protease to release an intracellular domain acting as a nuclear transcription regulator. Most ADAMs feature a significant overlap of substrate specificities, explaining why an inactivation of individual ADAMs only rarely causes major phenotypes.
Tomita, T. and T. Iwatsubo (2006). "gamma-secretase as a therapeutic target for treatment of Alzheimer's disease." Curr Pharm Des 12(6): 661-70.
Alzheimer's disease (AD) is the most common cause of dementia with aging, that is pathologically characterized by senile plaques that contain amyloid-beta peptides (Abeta) and neurofibrillary tangles comprised of phosphorylated tau. Genetic and biological studies provide evidence that the production and deposition of Abeta contribute to the etiology of AD. gamma-Secretase is the pivotal enzyme in generating the C terminus of Abeta, that determines its aggregability and propensity for deposition. Drugs that regulate the production of Abeta by inhibiting gamma-secretase activity could provide an effective therapeutics for AD, although recent studies suggest that gamma-secretase plays important roles in novel signaling pathways that play essential roles in embryonic development. This review focuses on recent progresses in the gamma-secretase biology that shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme. Moreover, we review the recent development of inhibitors and provide a direction for the effective treatment of AD through inhibition of gamma-secretase activity.
Thompson, J. (2006). "Vitamins and minerals 4: overview of folate and the B vitamins." Community Pract 79(6): 197-8.
Many studies have suggested that elevated homocysteine levels are an independent risk factor for cardiovascular disease, stroke and Alzheimer's disease. Lower levels of the three water-soluble vitamins--folate (folic acid), vitamin B6 and vitamin B12--are primary determinants of high blood homocysteine levels. In the fourth of an occasional series on vitamins, minerals and supplements, June Thompson looks at the role folate, in particular, may play in reducing homocysteine in the body and in protecting the body from some other diseases.
Thomas-Anterion, C. and B. Laurent (2006). "[Neuropsychological markers for the diagnosis of Alzheimer's disease]." Rev Neurol (Paris) 162(10): 913-20.
Better knowledge of the preclinical phase of Alzheimer's disease and of the symptomatic pre-dementia stage designated "mild cognitive impairment" will require considerable progress in our understanding of neuropsychological processes. The results of studies suggest that impaired performance in memory tests may serve as a marker for Alzheimer's disease. The best current predictors include stringent tests of episodic memory and recognition tests. The early stages of Alzheimer's disease also seem to involve subtle deficits in semantic memory and attentional processes. Face recognition and denomination seem to be useful tools. Greater accuracy and precision in the transitional zone between healthy aging and the first manifestations of Alzheimer's disease will require work combining data on neuropsychological profiles and neuroimaging.
Thirumangalakudi, L., P. G. Samany, et al. (2006). "Angiogenic proteins are expressed by brain blood vessels in Alzheimer's disease." J Alzheimers Dis 10(1): 111-8.
Data are emerging to support the idea that mediators of angiogenesis are found in the Alzheimer's disease (AD) brain. The objective of this study is to compare the expression of the angiogenic mediators vascular endothelial growth factor (VEGF), angiopoietin, and matrix metalloproteinases (MMPs) in the microcirculation of AD patients and age-matched controls. Our results indicate that angiopoietin-2 and VEGF are expressed by AD- but not control-derived microvessels. AD-derived microvessels also release higher levels of MMP-2 and MMP-9 compared to controls. The data show that despite high levels of MMP-9, assessed by western blot, MMP-9 activity is not detectable in AD microvessels. In this regard we find high levels of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in AD, but not control vessels. Furthermore, we explore the ability of thrombin, previously shown to be present in AD microvessels, to affect TIMP expression in cultured brain endothelial cells and find that thrombin causes up regulation of TIMP-1. These data show that angiogenic changes occur in the microcirculation of the AD brain and suggest that if these changes are contributory to disease pathogenesis, targeting the abnormal brain endothelial cell would provide a novel therapeutic approach for the treatment of this disease.
Thatcher, G. R., B. M. Bennett, et al. (2006). "NO chimeras as therapeutic agents in Alzheimer's disease." Curr Alzheimer Res 3(3): 237-45.
NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.
Thal, L. J., K. Kantarci, et al. (2006). "The role of biomarkers in clinical trials for Alzheimer disease." Alzheimer Dis Assoc Disord 20(1): 6-15.
Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.
Thal, D. R., E. Capetillo-Zarate, et al. (2006). "The development of amyloid beta protein deposits in the aged brain." Sci Aging Knowledge Environ 2006(6): re1.
The deposition of amyloid beta protein (Abeta) in the human brain and the generation of neurofibrillary tangles are the histopathological hallmarks of Alzheimer's disease. Accumulation of Abeta takes place in senile plaques and in cerebrovascular deposits as a result of an imbalance between Abeta production and clearance. This Review describes the different types of Abeta deposits, which can be distinguished by their morphology and by the hierarchical involvement of distinct areas of the brain in Abeta deposition. The role of intracellular Abeta in Abeta deposition and the mechanism of Abeta toxicity are also discussed.
Thal, L. J. (2006). "Prevention of Alzheimer disease." Alzheimer Dis Assoc Disord 20(3 Suppl 2): S97-9.
The prevention of Alzheimer disease (AD) remains an important goal because of its high prevalence in our society and its associated costs